Biomedical Engineering Reference
In-Depth Information
SCHEME 6.9
Exemplificative B/C/P approach to bicyclic scaffolds using selected proline
analogs.
synthesis, of a wide variety of highly substituted lactam-containing peptidomimetic
scaffolds through the synthesis and use of a remarkably stable and versatile class
of resin-bound aldehyde intermediates. The amino aldehyde was easily prepared by
ozonolysis of a
-amino acid containing an allyl group as the side chain. The skeletal
diversity coming from this approach was demonstrated by preparing a representative
series of five peptidomimetic scaffolds, consisting of lactones, lactams, bicyclics,
tricyclics, and tetracyclics (Scheme 6.10). In every case, the release of final prod-
ucts from resin is by a cyclative cleavage process, which also removed the need
for resin-linker handles that remained on the products. As representative examples,
five-membered lactams were formed by reductive amination, followed by cyclative
cleavage to form the amide bond. Similarly, cysteine was used to react with the alde-
hyde group to produce a thiazolidine ring, followed by generation of the final bicyclic
scaffold by cyclative cleavage to generate the amide bond (Scheme 6.11).
Similarly, Garcıa-Cuadrado et al. reported a paper on the generation of skeletal
diversity using the chemistry of amino aldehydes according to a couple/cyclization
process, and leading to diverse heterocycles in four steps containing up to five points of
diversity [26]. Specifically, a concise synthetic strategy consisting of a Petasis three-
component reaction followed by a tandem aza-Cope-Mannich cyclization was devel-
oped. Alternative iminium cyclization based on a Pictet-Spengler reaction or aminal
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